The present invention relates generally to an improved method of treating a patient diagnosed with congestive heart failure (CHF) or, as the disorder is often termed, chronic heart failure, by stimulating the patient's vagus nerve with a pattern and rate of stimulating pulses controlled by a thoracic impedance derived solely from cardiac signals generated by electrical energy of the patient's heart as the heart is undergoing its cardiac cycle. The invention encompasses evaluation of progression of CHF of the particular patient of interest, and treating the patient by vagal stimulation (VS) from an implanted neurostimulator whose output is controlled according to the impedance and ventilation of the patient to appropriately adjust the patient's heart rate in a correlated manner so as to alleviate the CHF.
Specific resistance of biological materials and impedance measurements have played a major role in modern medicine. The electrical conductivity and capacity of disperse systems have been described as early as 1931 (Fricke et al., The Electric Conductivity of and Capacity of Dispersed Systems; Physics 1931; 1:106-115). Later, especially in the 1950s and 1960s, significant interest was directed towards the resistance of biological materials (e.g., Geddes L. et al., The Specific Resistance of Biological Material: A Compendium of Data for the Biomedical Engineer and Physiologist, Medical and Biological Engineering 1967, 5:271-293). The application of impedance and resistance measurements for cardio-circulatory function by measuring the blood and body temperature has been studied extensively by Geddes et al., Medical and Biological Engineering 1967, 11:336-339). Also, internal and external whole body impedance measurements have been used for noninvasive monitoring and determination of cardiac output (Carter et al., Chest 2004, 125:1431-1440). In addition, the feasibility of using intracardiac impedance measurements has been evaluated by E. Alt et al. for capture detection in connection with cardiac pacing (Pace 1992, 15:1873-1879).
Background patents that describe the use of impedance in conjunction with implantable devices are referenced in U.S. Pat. No. 5,003,976 to Alt, which describes the cardiac and pulmonary physiological analysis via intracardiac measurements with a single sensor. The '976 patent discloses that a single functional parameter, namely intracardiac impedance, varies both with the intrathoracic pressure fluctuations following respirations and with cardiac contraction. This value is representative of both pulmonary activity and cardiac activity. The finding indicates that this information derived from intracardiac impedance can be used not only to monitor the patient's cardiac and pulmonary activity, condition and cardio-circulatory status, but also, to control the variability of the rate of an implantable cardiac pacemaker.
U.S. Pat. No. 4,884,576 to Alt et al. discloses a self-adjusting rate responsive cardiac pacemaker and method based on the intracardiac signal derived from impedance measurements using an electrode implanted into the heart. And U.S. Pat. No. 4,919,136, also to Alt, describes a ventilation controlled pacemaker which uses the ventilation signal derived from those impedance measurements with an electrode in the heart to adjust the pacing rate.
Recently, considerable interest has been focused on the monitoring of congestive heart failure by means of impedance. U.S. Pat. No. 6,473,640 to Erlebacher describes a system that detects changes in resistance to a flow of current in the systemic venous system, and detects changes in impedance to a flow of current through lungs. The specific signal processing enables a determination of congestion in the venous or in the pulmonary system by application of differential signal processing of impedance. Other methods, such as are described by Combs in U.S. Pat. No. 5,957,861 and Riff in U.S. Pat. No. 5,876,353, respectively pertain to impedance monitoring for discerning edema through evaluation of respiratory rate, and use of implantable medical devices for measuring time varying physiological conditions, especially edema, and for responding thereto.
U.S. Pat. No. 6,104,949 to Pitts-Crick relates to a device and a method used for the diagnosis and treatment of congestive heart failure. Godie, in U.S. Pat. No. 6,351,667, describes an apparatus for detecting pericardial effusion, in which a wire probe anchored to the right heart ventricle and two other wire probes are used to measure the impedance between the different probes in order to assess the degree of pericardial effusion.
U.S. Pat. No. 4,899,758 to Finklestein et al describes a method and apparatus for monitoring and diagnosing hypertension and congestive heart failure. U.S. Pat. No. 6,336,903 to Brody relates to an automatic system and method for diagnosing and monitoring congestive heart failure and the outcomes thereof. U.S. patent publication 2002-0115939 to Moligan et al describes an implantable medical device for monitoring congestive heart failure in which incremental changes in parameter data over time provide insight to the patient's heart failure state.
The measurement of heart failure becomes of greater clinical interest and importance as more than 5 million patients in the U.S. are affected. With deterioration of myocardial function, patients often require repeated hospitalization. Current methods of monitoring congestive heart failure cannot reliably predict an early occurrence of this congestive heart failure; but an understanding of its occurrence may provide an early indicator of this adverse event for the patient.
A considerable number of new treatment forms have been introduced into clinical practice. It had been shown that congestive heart failure can be treated, not only by drugs, especially Beta blockers, but also by biventricular pacing. This method makes use of the exact timing of a stimulus, not only to the right ventricle or to the septum, but also to the left side of the heart by means of an electrode which is implanted into the coronary venous circulation. By these means, the left ventricle can be stimulated at a time that provides an optimal synchronization of the heart and improves the mechanical effectiveness of the systole by synchronizing the depolarization of the right heart, the septum and the left heart. This avoids the ineffective late contraction of the left ventricle at a time when the septum depolarization has already occurred, and the squeezing of the blood by synchronous action of the septum and left ventricle is no longer present. In addition, the reduction in mitral valve regurgitation by this type of resynchronization has been shown.
Studies published at the 2005 meeting of the American College of Cardiology in Orlando, Fla., USA (CARE-HF study) illustrate that not only the quality of life of those patients with New York Heart Association, Heart Failure Class 3 and 4 can be improved, but also the life expectancy. This recent data show very impressively that over a 3-year period such biventricular stimulation and the mortality can be reduced by half in a highly significant manner. All these new devices improve the survival and quality of life of patients and have a beneficial effect on re-hospitalization. Nevertheless, the occurrence of heart failure is still a major problem for these patients, and it is beneficial to detect such a heart failure as early as practicable.
Accurate adjustment of heart rate also plays a major role in patients with implantable devices, such as pacemakers and defibrillators. Rate adaptive pacemakers in the past have provided an open type of correlation between a signal parameter to adjust the heart rate and the affected heart rate. However, even multiple sensor parameters that have been used for adjustment of the pacing rate have not brought the real need of a patient to clinical practice, mainly a closed-loop monitoring of heart rate.
In the healthy person, the heart rate is regulated by a very sophisticated closed loop and negative feedback. Heart rate only increases to a level with exercise which is physiologically beneficial. This means that if a patient exercises only mildly, his heart rate increases proportional to the increase in oxygen uptake for this person which is a fraction of his maximum exercise capacity, maximum oxygen uptake and aerobic and anaerobic capacity. Thus, if someone is well-trained, an external load of 50 watts might represent only 25% of his/her maximum exercise capacity if the patient is capable of exercising up to a level of 200 watts. With this external load of 50 watt the heart rate will increase by only the fraction that is represented by the patient's resting heart rate and maximum exercise heart rate. In other words, such a well-trained person will increase his/her heart rate only by 30-35 beats per minute (bpm). A less capable patient who has a maximum exercise capacity of 100 watts, will increase his/her heart rate with the same external load to a higher degree. In that case, the slope of increase in heart rate depends not only on a fixed relation of a sensor parameter, such as ventilation or physical activity or any other physiologic parameter having a suitable correlation with heart rate, but also on his/her underlying cardio-pulmonary exercise capacity and condition.
According to Motonori Ando et al (Circulation 2005; 112: 164-170), stimulation of the vagus nerve can exert antiarrythmogenic effects during acute myocardial ischemia. While the Ando paper refers to studies conducted on rats, the authors postulate that human patients may benefit from such effects of vagal stimulation, which are accompanied by prevention of the loss of phosphorylated Cx43 during acute myocardial ischemia. Cx43 is a subtype of connexins Cx, highly homologous proteins which compose gap-channel junctions that have been implicated in the electrical coupling of excitable tissues, such as cardiac muscles. Cx40 is a second subtype of connexins in the adult heart muscle but is primarily found in atrial tissue, whereas Cx43 is predominantly expressed in ventricular tissue.
According to other studies cited by Ando et al in their paper, the protein content of ventricular Cx43 is remarkably reduced in ischemia and heart failure, and this reduced expression of Cx43 increases the incidence of ventricular tachyarrythmias and reduces the conduction velocity during acute myocardial ischemia. These results, they say, suggest that the loss or dysfunction of Cx43 in cardiomyocytes may be one of the mechanisms that promote lethal ventricular tachyarrythmias, including ventricular fibrillation.
Studies reported prior to that of Ando et al demonstrated that ventricular arrhythmia is one of the major causes of death in chronic or congestive heart failure. It is reported that VS therapy markedly improved long term survival in an animal model of chronic heart failure after myocardial infarction (see, e.g., Meihua Li et al, “Vagal nerve stimulation markedly improves long-term survival after chronic heart failure in rats,” Circulation 2003; 109: 120-124; and Correspondence in the same publication concerning a query raised by Springer et al on the latter study as to whether VS provides an anti-inflammatory intervention in CHF, and response thereto by Li et al, op. cit.; e34).
While the mechanisms of VS on myocardial infarction are not known, Ando et al postulate that the antiarrhythmogenic effects and accompanying prevention of the loss of Cx43 exerted by VS during acute myocardial ischemia play a critical role in improving ischemia-induced cellular electrical instability of ventricular myocytes. VS has also been postulated to contribute to an antifibrillatory effect.
In U.S. Pat. No. 6,622,041 (“the '041 patent”), incorporated by reference in its entirety herein, Terry et al describe a method of treating CHF and autonomic cardiovascular drive disorders, in which an implanted neurostimulator is used to apply stimulating electrical pulses in a predetermined pattern and rate to the patient's vagus nerve at or above the cardiac branch of the nerve. The neurostimulator is designed to sense the patient's heart rate from an electrode or array engaging or proximate the nerve as the basis for controlling the vagal stimulation. The stimulating pulse rate is varied according to the physical status of the patient, that is, at rest or engaged in physical exertion, albeit moderate, so as to respectively reduce or increase the patient's heart rate relative to the normal resting rate. The physical state of the patient in this respect is detected by a metabolic need sensor, such as an accelerometer, which may be housed within the same case as, and operatively coupled to the neurostimulator. Terry et al hypothesize that this VS treatment can reduce the occurrence and the symptoms of heart failure and improve the cardiac output of the heart.
Terry et al refer to studies reported by Klamath (Pace 1992; 15: 1581-1587) on the neurocardiac responses to vagoafferent electrostimulation in patients for the control of epilepsy, which indicated that stimulation of the vagus nerve below the superior cardiac branch can have a long term beneficial effect on the balance of the sympathetic/parasympathetic system, and serve to demonstrate the feasibility of using vagus nerve stimulation to provide the heart with adequate parasympathetic support to promote natural healing.
The '041 patent describes stimulating the vagus nerve either above its cardiac branch or at the cardiac branch at a rate determined to limit the upper heart rate of the patient to a physiologically safe limit. Vagal stimulation below the cardiac branch will not affect heart rate to the same extent. The cervical cardiac branch of the vagus nerve provides the most convenient access location for attaching the stimulating electrode because of where the branch from the main trunk of the vagus is located in the patient's neck, providing a desirably long section in the neck from which to select a site for electrode attachment.
The vagal stimulation pulse frequency or rate at the site has an inverse effect on the heart rate, and may be experimentally determined and appropriately adjusted to achieve a particular heart rate for each patient during a treadmill test. Terry et al stress the need for each of the VS rates to be verified by the patient's attending physician to assure the propriety of a prescribed target heart rate for that patient.
As an example cited in the '041 patent, stimulation may be commenced whenever the heart rate exceeds a predetermined threshold, such as 90 BPM. Alternatively, the stimulation rate may be adjusted automatically to maintain the heart rate within a specified range. Another alternative specified in the '041 patent is to synchronize the vagal stimulation to the P or R wave of the patient's EKG, and deliver a burst delayed from the synchronizing signal. The right vagus nerve is preferred for stimulation because it is more responsive to synchronized heart pacing, but the left vagus nerve may be used instead. The burst duration is approximately 100 msec. The stimulation rate, burst duration, and delay from the synchronization point is programmed to limit the heart rate within a desired range; for example, 60 to 150 BPM. An exemplary VS pulse burst is delivered with a delay of 100 msec from the P wave. Heart rate should be monitored and burst mode parameters, specifically burst frequency, should be adjusted automatically to protect the patient from patterns which could produce a heart rate lower than a physiologically safe level.
Left or right cardiac vagal stimulation at a predetermined rate selected to lower the resting heart rate by a specified percentage, such as 10%-45%, is contemplated to allow more time for the heart muscle to repair during muscle contractions, according to Terry et al. It is also contemplated to be beneficial in stimulating the growth of additional coronary capillaries, so as to supply more blood to the heart muscle, and may also be beneficial in dilating the coronary vessels further increasing coronary blood flow, to aid in recovery and strengthening of the heart muscle. When a metabolic need for increased heart rate is indicated in the neurostimulator of the '041 patent, the device programming causes VS cessation or sufficient reduction so that the patient's intrinsic heart rate may increase, but not exceed an upper rate limit.
In the '041 patent, the metabolic need sensor is adapted to inhibit or control the VS rate to produce a target heart rate within the physician-prescribed limits.
The disclosure of the aforesaid related co-pending U.S. patent application Ser. No. 12/857,140 (“the '140 patent application”) pertains to sensing cardiac signals generated by electrical energy of the heart of a patient of interest, applying the sensed cardiac signals as the sole input to signal detection circuitry and from which a factor or parameter related to thoracic impedance of the patient is derived, and to changes in the thoracic impedance, as an indication of the status of a physical condition of the patient and, if present, an abnormality thereof.
Reported attempts to determine impedance measurements from internal signals in the body prior to the '140 patent application had used external power sources to stimulate the heart or to provide currents through the thorax, sensed the resulting cardiac signals or current amplitudes in the thorax, and applied them to detection devices for monitoring and measuring impedance. This external energy could be applied either outside the thorax from a supply external to the body, or by an implantable device that uses energy from a battery housed within the device itself.